In human, estrogen replacement therapy (ERT) improves memory performance in ovariectomized (OVX) and post-menopausal women and is thought to decrease the risk of Alzheimer's disease. Changes in circulating levels of estrogen in rat affect the synaptic properties of hippocampal circuits that mediate memory, and these effects appear to be NMDA receptor-dependent. In addition, a high degree of NMDA receptor plasticity occurs in response to aging and estrogen manipulations in hippocampus that is cell class- and circuit-specific. In collaboration with the other four Projects and Core A, this Project will employ both rat and non-human primate models to develop a comprehensive animal model of the impact of estrogen depletion and ERT on NMDA receptors and hippocampal circuits with respect to memory performance. The degree to which the impact of estrogen on these circuits is comparable in young and old female rats and monkeys will also be investigated. Several relevant neurobiological parameters will be analyzed and compared in ovariectomized (OVX) animals with and without ERT, as well as in aged monkeys that are pre- and post-menopausal. In Specific Aims 1-3, morphologic parameters such as neuron number, dendritic arbor, and spine density will be analyzed, as well as quantitative confocal microscopy, and post-embedding immunogold electron microscopy will be used to de3velop a quantitative database of these parameters in OVX versus OVX with ERT in old and young adult females of both species. In Specific Aim 4, the most robust and functionally relevant morphologic and neurochemical attributes that are responsive to estrogen in S.A.s 1-3 will be considered in relation to behavioral parameters in monkeys that have been tested for memory performance and attention in Project 5. In collaboration with Project 2, Specific Aim 3 will investigate the most robust morphologic and neurochemical effects of OVX and ERT in animals 25-28 years old that are either still cycling or post-menopausal, in order to drawl parallels between surgically induced and naturally occurring menopause. This comprehensive approach will delineate the interactions among estrogen levels, hippocampus, NMDA receptors, memory, and aging and lay the groundwork for more informed approaches to ERT in humans with respect to the neurologic and behavioral manifestations.